The Proteoglycan Lectin Domain Binds Sulfated Cell Surface Glycolipids and Promotes Cell Adhesion

Abstract

The lecticans are a group of chondroitin sulfate proteoglycans characterized by the presence of C-type lectin domains. Despite the suggestion that their lectin domains interact with carbohydrate ligands, the identity of such ligands has not been elucidated. We previously showed that brevican, a nervous system-specific lectican, binds the surface of B28 glial cells (Yamada, H., Fredette, B., Shitara, K., Hagihara, K., Miura, R., Ranscht, B., Stallcup, W. B., and Yamaguchi, Y. (1997) J. Neurosci. 17, 7784 -7795). In this paper, we demonstrate that two classes of sulfated glycolipids, sulfatides and HNK-1-reactive sulfoglucuronylglycolipids (SGGLs), act as cell surface receptors for brevican. The lectin domain of brevican binds sulfatides and SGGLs in a calcium-dependent manner as expected of a C-type lectin domain. Intact, full-length brevican also binds both sulfatides and SGGLs. The lectin domain immobilized as a substrate supports adhesion of cells expressing SGGLs or sulfatides, which was inhibited by monoclonal antibodies against these glycolipids or by treatment of the substrate with SGGLs or sulfatides. Our findings demonstrate that the interaction between the lectin domains of lecticans and sulfated glycolipids comprises a novel cell substrate recognition system, and suggest that lecticans in extracellular matrices serve as substrate for adhesion and migration of cells expressing these glycolipids in vivo.The lecticans are a family of chondroitin sulfate proteoglycans (CSPGs) 1 characterized by the presence of a C-type lectin domain in their core proteins (1, 2). The C-terminal globular domains of lecticans, or "proteoglycan lectin domain" (PLD), consist of one or two epidermal growth factor (EGF)-like domains, a C-type lectin domain, and a complement regulatory protein (CRP) domain. This arrangement of domains is similar to that of selectins, suggesting that lecticans are also involved in the recognition of carbohydrate ligands.Lecticans are the most abundantly expressed family of proteoglycans in the nervous system. The lectican family includes aggrecan (3), versican (4), neurocan (5), and brevican (6), all of which are expressed in the nervous system at certain stages of development (1, 7). Although aggrecan and versican were initially characterized as connective tissue proteoglycans, their expression in the nervous system has been demonstrated in a number of reports (8 -12). Brevican and neurocan are specifically expressed in the nervous system (6, 13-15). Structural similarities with selectins and the abundant expression in the nervous system suggest that lecticans play major roles in carbohydrate recognition in the nervous system.The identity of the ligand to PLDs has been a focus of our interest. We previously showed that the PLD of versican binds tenascin-R, an extracellular matrix (ECM) protein predominantly expressed in the nervous system (16). More recently, we demonstrated that the PLDs of all lecticans bind tenascin-R, and that brevican and tenascin-R indeed form a complex in adult rat brain e...

Versican Mediates Mesenchymal-Epithelial Transition

“…CS chains are absent in the versican V3 isoform. The G1 domain of versican binds hyaluronan (LeBaron et al, 1992), whereas the G3 domain not only interacts with extracellular matrix (ECM) proteins (Zheng et al, 2004b;Wu et al, 2005b), but also interacts with sulfated glycolipids (Miura et al, 1999). Interaction of versican with ECM and cell surface proteins is believed to provide structural integrity to tissues and regulate cell proliferation and differentiation.…”

A Hyaluronan Binding Link Protein Gene Family Whose Members Are Physically Linked Adjacent to Chrondroitin Sulfate Proteoglycan Core Protein Genes

“…These aggregates can interact with numerous other ECM and cell surface components through binding interactions of the CSPG core protein, the chondroitin sulfate and/or the HA chain. Binding partners that have been identified to date, include HA receptors such as CD44 (11), EGF receptors (12), sulfated glycolipids (13), tenascins (14,15), fibulins (16), and neural cell adhesion molecule (15,17). Therefore, the HA-CSPG aggregate, although present at relatively low levels in many tissues, may provide an important nucleus within the ECM and PCM around which an extensive matrix can be organized.…”

Alternative Splicing in the Aggrecan G3 Domain Influences Binding Interactions with Tenascin-C and Other Extracellular Matrix Proteins

“…tenascin-R (14,15), fibulin-1 (16), fibulin-2 (17), and fibrillin-1 (18). The G3 domain also binds sulfated glycolipids on the cell surface (19). In addition, neurocan has been reported to bind to tenascin-C (20).…”